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The PSA (KLK3) genetic variant rs17632542 is associated with reduced prostate cancer risk and lower serum PSA levels, although the underlying reasons are unclear. Here, the authors show that this PSA variant reduced proteolytic activity and leads to smaller tumours, but also increases invasion and bone metastasis, indicating its dual risk association depending on tumour context; the variant is associated with both lower risk and poor clinical outcomes.

Antimicrobial peptide LL37 can bind nucleic acids and potentiate their sensing by endosomal TLRs. Here the authors show that LL37 binds to RNA from neutrophil extracellular traps (NETs), which amplifies inflammation and production of more LL37 and NETs via TLR8/13, suggesting that LL37 contribution to psoriasis may be fueled by NET-associated RNA.

High salt intake changed the gut microbiome and increased T_H17 cell numbers in mice, and reduced intestinal survival of Lactobacillus species, increased the number of T_H17 cells and increased blood pressure in humans.

There is limited data on how SARS-CoV-2 antivirals compare regarding efficacy and blocking transmission. Here, treating dwarf hamsters and ferrets with either molnupiravir or paxlovid the authors find comparable efficacy against severe COVID-19-like disease and complete block of transmission by molnupiravir.

Integration of mathematical modeling, ecological analyses of patient biopsies, and neoantigen heterogeneity suggests recruitment of immunosuppressive cells is key to initializing transformation from adenoma to carcinoma in human colorectal cancer.

Arthritis affects different joints variably despite systemic inflammatory cues. Here the authors show anatomical differences in the transcriptome, epigenome and function of synovial fibroblasts that might affect susceptibility to site-specific joint diseases.

This study investigates how homeostatic mechanisms endow sensory representations in the auditory cortex with resilience against neuron loss. The map of sounds has the ability to recover after microablation by recruiting previously unresponsive neurons.

Inhibition of cyclooxygenase 1 releases T cells from immunosuppression by platelet-derived thromboxane A₂, thereby enhancing the immune response against metastasis.

Type I IFN has apposing effects in neuromyelitis optica spectrum disorder (NMOSD) and multiple sclerosis (MS). Here the authors perform molecular profiling of NMOSD patients and mouse mechanistic experiments of neuro-inflammation to show that IFN-I stimulates pathogenic Th17 via IL-6 production by B cells.

While dimethylarginine dimethylaminohydrolase 1 (DDAH1) is known to metabolize the endogenous inhibitor of nitric oxide synthases, asymmetric dimethylarginine (ADMA), the function of DDAH2 has remained controversial. Here, the authors present several lines of evidence that DDAH2 does not hydrolyze ADMA.

Heeren et al study the evolutionary genomics of leishmaniasis in Peru and Bolivia to show that parasite hybridization increases the prevalence, diversity and spread of viruses that have been previously associated with disease severity and treatment failure.

Immune checkpoint inhibitors (CPI) could effectively target cancers that are resistant to traditional therapy but may initiate immune related adverse effects, such as colitis. Here, authors characterise the gut immune microenvironment during CPI-colitis by bulk RNA sequencing, single-cell RNA sequencing and flow cytometry, and find that interleukin 23 plays an important role in promoting inflammation via cytotoxic polyfunctional IFNγ-producing lymphocytes.

Eosinophils are traditional immune effectors involved in tissue homeostasis. In this study, eosinophils emerge as key regulators of bone homeostasis by interacting with osteoclasts, inhibiting their differentiation and pathological bone loss.

Cell migration regulates diverse (patho)physiological processes, including cancer metastasis. Here the authors show that the chloride ion channel SWELL1 and the ion exchanger NHE1 are preferentially enriched at the trailing and leading edges, respectively, of migrating cells and regulate cell volume to propel confined cells, favouring breast cancer cell extravasation and metastasis.

Understanding the immune response to SARS-CoV-2 is dependent on being able to distinguish COVID-19 immune responses from cross-reactive immune responses to other coronaviruses. Here the authors show that choice of antigens and whether an ICS, ELISPOT or T cell proliferation assay is used has a major effect on this discriminatory ability.

Neurotrophin receptor TrkB regulates neuronal growth and neuroplasticity. Here, the authors present the NMR structure of the intramembrane region of TrkB activated by antidepressant drugs, yielding insights into receptor function.

Hofer et al. show that fasting promotes the synthesis of spermidine, which stimulates eIF5A hypusination to induce autophagy and increase lifespan in various species in a conserved manner.

The activation and accumulation of lung fibroblasts resulting in aberrant deposition of extracellular matrix components is a pathogenic hallmark of idiopathic pulmonary fibrosis. Here, the authors show that the formation of podosomes in lung fibroblasts stimulates extracellular matrix invasion in a mouse model of the disease, suggesting that pharmacological targeting of podosome formation or organization might be a therapeutic option.

The transcription factor CREM is a pivotal regulator of NK cell function, making CREM a valuable target to increase the efficacy of anticancer immunotherapies based on this cell population and chimeric antigen receptors.

Here the authors show that codependence of dynein and kinesin KIF1C occurs through binding of the FTS–HOOK3–FHIP1B cargo adapter. Binding of KIF1C releases the HOOK3 autoinhibited folded conformation allowing dynein to bind the adapter. In this cocomplex, KIF1C further acts as a processivity factor for dynein.

The authors report a meta-analysis of methylome-wide association studies, identifying 15 significant CpG sites linked to major depression, revealing associations with inflammatory markers and suggesting potential causal relationships through Mendelian randomization analysis.

Engineered Mycobacterium bovis BCG encoding tetracycline-controlled phage lysin kill switches elicits protective immunity against subsequent M. tuberculosis infection in mice and non-human primates.

Genome-wide association analyses identify new risk loci for heart failure and its subtypes, extending understanding of the underlying biological pathways and disease mechanisms.

Repetitive transcranial magnetic stimulation (rTMS) is widely used as a therapeutic tool yet its effect on inhibitory networks in the brain has not been studied. Here, the authors demonstrate that 10Hz rTMS specifically reduces dendritic inhibition onto pyramidal neurons accompanied by remodeling of postsynaptic gephyrin clusters.

The ubiquitin ligase, RNF168, promotes DNA break repair but must be regulated to prevent run-away ubiquitin signaling. Here, the authors identify a three-step post-translational cascade regulating RNF168 chromatin removal, acting to suppress excessive signaling and radiosensitivity.

The mechanism of neurovascular coupling ensures that the brain energy supply is sufficient to meet demand. Here the authors show that in this mechanism CO2 plays an important role in neuronal activity-dependent regulation of local brain blood flow.

Döring, van der Vorst, Yan, Neideck et al. present a non-canonical chemokine pathway involving CCL17 signaling through CCR8, which induces CCL3 expression independent of CCR4 and suppresses the functions of atheroprotective T_reg cells.

The lineage of human epicardium is studied using time course single-cell analysis of epicardioids.

Microtubule tracks are important for the transport of molecules within axons. Here, the authors show that ATAT1, the enzyme responsible for acetylating a-tubulin, receives acetyl groups from ATP citrate lyase whose stability is regulated by Elongator, a protein mutated in the neuronal disease Familial dysautonomia.

A global network of researchers was formed to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity; this paper reports 13 genome-wide significant loci and potentially actionable mechanisms in response to infection.

A major challenge of enzyme-linked immunosorbent assays is discriminating true signal from non-specific binding. Here the authors present a Single-Molecule Colocalization Assay (SiMCA) which eliminates such effects, enabling reproducible detection of picomolar protein concentrations.

Here, Tain et al. describe the genetic interaction between 4E-BP, an inhibitor of translation, with Parkinson's disease–associated park and Pink1 in Drosophila, where the manipulation of 4E-BP reduced the pathologic phenotypes, including degeneration of dopaminergic neurons, in park and Pink1 mutant flies.

Hexa-acylated lipopolysaccharides from the gut microbiota are associated with efficacy in patients with cancer receiving anti-PD-1 and stimulate host immune activation for enhanced anti-tumour immunity in mouse models.

Epstein–Barr virus infection generates a neuroinvasive B cell subset, which recruits activated T cells to the central nervous system, promoting multiple sclerosis.

A study of mice exposed to cigarette smoke suggests that smoking-cessation-induced weight gain is associated with a dysbiotic state that is driven by smoking-related metabolites.

Certain RIFINs from Plasmodium falciparum can bind to both inhibitory (KIR2DL1) and activating (KIR2DS1) immune receptors on natural killer cells, demonstrating the potential role of activating killer immunoglobulin-like receptors in targeting pathogens and controlling malaria infection.

Horizontal gene transfer in bacteria can occur through mechanisms such as conjugation, transduction and transformation, which facilitate the passage of DNA across the cell wall. Here, Kapteijn et al. show that cell wall-deficient bacteria can take up DNA and other extracellular materials via an endocytosis-like process.

The ability to encode and recall information about food is critical for survival. We reveal that ventral hippocampus projections to the lateral hypothalamus encode meal-related memories, and that disruption of this circuit promotes excessive eating.

In lung adenocarcinoma, antibodies against endogenous retroviruses promote anti-tumour activity, and expression of endogenous retroviruses can predict outcomes of immunotherapy.

The human leukocyte antigen (HLA) haplotype DRB1*15:01 is the major risk factor for multiple sclerosis (MS).  Here the authors find that DNA methylation at HLA-DRB1 gene mediates the effect of DRB1*15:01 and of a protective HLA variant on HLA-DRB1 expression and the risk of MS.

Directed evolution is a process of mutation and artificial selection to breed biomolecules with new or improved activity. Here the authors develop a directed evolution platform (PROTein Evolution Using Selection; PROTEUS) that enables the generation of proteins with enhanced or novel activities within a mammalian context.

Tissue fluidification in invasive breast carcinoma is accompanied by mechanical stresses that compromise nuclear integrity and liberate DNA, resulting in the activation of a pro-inflammatory response that shape tumour evolution and progression.

Aedes aegypti transmit several arboviruses and control of the mosquito populations could be beneficial. Here the authors show that deletion of leucine aminopeptidase1 (LAP1) results in mitochondrial defects and abnormal autophagy in sperm, reducing fertility and fecundity of females. LAP1^−/− males show no obvious defects in longevity and mating fitness.

Indole-3-acetic acid (3-IAA), a tryptophan metabolite derived from the gut microbiota, is associated with a better response to chemotherapy in pancreatic ductal adenocarcinoma (PDAC), and dietary interventions could have a role in the treatment of PDAC.

HnRNP R regulates the axonal transcriptome. Here the authors show that hnRNP R is a component of translation initiation complexes and interacts with O-linked β-N-acetylglucosamine (O-GlcNAc) transferase (Ogt), promoting O-GlcNAcylation of eIF4G.

The structure of a RIFIN–LILRB1 complex reveals that a subset of RIFINs of Plasmodium falciparum mimics the binding mode of the natural ligand of human LILRB1 and suppress the function of natural killer cells in humans.

Fatty liver disease exacerbates atherosclerosis, but the underlying mechanisms remain unclear. Here, the authors show that D-dopachrome tautomerase (D-DT/MIF-2) acts as an atypical chemokine, promoting both atherosclerosis and hepatic lipid accumulation.